Selectively targeting the cells that drive PF would protect the patients from systemic side effects associated with therapies. Two approaches were designed to target either fibrotic lung fibroblasts or pathogenic macrophages. A FAP-targeted PI3K inhibitor was created, which was shown to inhibit PI3K activation and decrease fibrotic markers in a mouse model of fibrosis. 

A folate-targeted TLR7 agonist (FA-TLR7-54) was developed to reprogram M2-like fibrosis-inducing macrophages into fibrosis-suppressing macrophages. Dramatic decreases in cytokine release, hydroxyproline levels, and collagen deposition were observed in animal model studies. These studies suggest that FAP-targeted PI3K inhibitors or folate-targeted TLR7 agonists may be promising treatments for pulmonary fibrosis. 

As a result of this work, two papers have been published:

• “Reprogramming of profibrotic macrophages for treatment of bleomycin-induced pulmonary fibrosis” was published in EMBO Molecular Medicine, 2020. You can find the article in the Publications page of this site or by clicking here.

• “Targeted inhibition of PI3 kinase/mTOR specifically in fibrotic lung fibroblasts suppresses pulmonary fibrosis in experimental models” appeared in Science Translational Medicine, October 2020. You can find the article in the Publications page of this site or by clicking here.

These studies were conducted in the labs of Philip S. Low, PhD, and Ivan Rosas, MD, supported by funding from Three Lakes Foundation. Dr. Low is Purdue’s Ralph C. Corley Distinguished Professor of Chemistry and Presidential Scholar for Drug Discovery. Ivan Rosas, MD, is Professor and Section Chief at Baylor College of Medicine.